Apparatus and method for cryogenic inhibition of hyperplasia

ABSTRACT

Post-angioplasty hyperplasia in blood vessels is treated using a cryosurgical balloon catheter. The balloon catheter is positioned at a target region within the blood vessel, and the balloon inflated by expanding a cryogenic fluid, such as liquid nitrogen, across an expansion orifice into a balloon. The balloon will be constructed so that cooling is achieved primarily in the central regions of the balloon, with the proximal and distal regions being less cold and acting to insulate adjacent regions of the blood vessel from excessive cooling.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of, and claims priority from U.S.patent application Ser. No. 09/203,011 filed Dec. 1, 1998 now U.S Pat.No. 6,355,029, which is a continuation-in-part of, and claims thebenefit of priority from, U.S. patent application Ser. No. 08/982,824,filed Dec. 2, 1997 now U.S. Pat. No. 5,971,979, the full disclosures ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to apparatus and methods forinhibiting restenosis in arteries following angioplasty or otherintravascular procedures for treating atherosclerotic disease. Moreparticularly, the present invention relates to apparatus and methods forcryogenically treating the target site within a patient's vasculature toinhibit hyperplasia which can occur after such intravascular procedures.

A number of percutaneous intravascular procedures have been developedfor treating atherosclerotic disease in a patient's vasculature. Themost successful of these treatments is percutaneous transluminalangioplasty (PTA) which employs a catheter having an expansible distalend, usually in the form of an inflatable balloon, to dilate a stenoticregion in the vasculature to restore adequate blood flow beyond thestenosis. Other procedures for opening stenotic regions includedirectional arthrectomy, rotational arthrectomy, laser angioplasty,stents and the like. While these procedures, particularly PTA, havegained wide acceptance, they continue to suffer from the subsequentoccurrence of restenosis.

Restenosis refers to the re-narrowing of an artery within weeks ormonths following an initially successful angioplasty or other primarytreatment. Restenosis afflicts up to 50% of all angioplasty patients andresults at least in part from smooth muscle cell proliferation inresponse to the injury caused by the primary treatment, generallyreferred to as “hyperplasia.” Blood vessels in which significantrestenosis occur will require further treatment.

A number of strategies have been proposed to treat hyperplasia andreduce restenosis. Such strategies include prolonged balloon inflation,treatment of the blood vessel with a heated balloon, treatment of theblood vessel with radiation, the administration of anti-thrombotic drugsfollowing the primary treatment, stenting of the region following theprimary treatment, and the like. While enjoying different levels ofsuccess, no one of these procedures has proven to be entirely successfulin treating all occurrences of restenosis and hyperplasia.

For these reasons, it would be desirable to provide additional apparatusand methods suitable for the treatment of restenosis and hyperplasia inblood vessels. It would be further desirable if the apparatus andmethods were suitable for treatment of other conditions related toexcessive cell proliferation, including neoplasms resulting from tumorgrowth, hyperplasia in other body lumens, and the like. The apparatusand method should be suitable for intravascular and intraluminalintroduction, preferably via percutaneous access. It would beparticularly desirable if the methods and apparatus were able to deliverthe treatment in a very focused and specific manner with minimal effecton adjacent tissues. Such apparatus and methods should further beeffective in inhibiting hyperplasia and/or neoplasia in the targettissue with minimum side affects. At least some of these objectives willbe met by the invention described hereinafter.

2. Description of the Background Art

Balloon catheters for intravascularly cooling or heating a patient aredescribed in U.S. Pat. No. 5,486,208 and WO 91/05528. A cryosurgicalprobe with an inflatable bladder for performing intrauterine ablation isdescribed in U.S. Pat. No. 5,501,681. Cryosurgical probes relying onJoule-Thomson cooling are described in U.S. Pat. Nos. 5,275,595;5,190,539; 5,147,355; 5,078,713; and 3,901,241. Catheters with heatedballoons for post-angioplasty and other treatments are described in U.S.Pat. Nos. 5,196,024; 5,191,883; 5,151,100; 5,106,360; 5,092,841;5,041,089; 5,019,075; and 4,754,752. Cryogenic fluid sources aredescribed in U.S. Pat. Nos. 5,644,502; 5,617,739; and 4,336,691.

The full disclosures of each of the above U.S. patents are incorporatedherein by reference.

SUMMARY OF THE INVENTION

The present invention comprises the cryosurgical treatment of a targetsite within the body lumen of a patient, usually in an artery which hasbeen previously treated for atherosclerotic disease by balloonangioplasty or any of the other primary treatment modalities describedabove. The present invention, however, is further suitable for treatingother hyperplastic and neoplastic conditions in other body lumens, suchas the ureter, the biliary duct, respiratory passages, the pancreaticduct, the lymphatic duct, and the like. Neoplastic cell growth willoften occur as a result of a tumor surrounding and intruding into a bodylumen. Inhibition of such excessive cell growth is necessary to maintainpatency of the lumen.

Treatment according to the present invention is effected by coolingtarget tissue to a temperature which is sufficiently low for a timewhich is sufficiently long to inhibit excessive cell proliferation. Thecooling treatment will be directed against all or a portion of acircumferential surface of the body lumen, and will preferably result incell growth inhibition, but not necessarily in significant cellnecrosis. Particularly in the treatment of arteries following balloonangioplasty, cell necrosis may be undesirable if it increases thehyperplastic response. Thus, the present invention will slow or stopcell proliferation but may leave the cells which line the body lumenviable, thus lessening hyperplasia.

Methods according to the present invention comprise cooling an innersurface of the body lumen to a temperature and for a time sufficient toinhibit subsequent cell growth. Generally, the temperature at the tissuesurface will be in a range from about 0° C. to about −80° C., the tissuesurface temperature preferably being in a range from about −10° C. toabout −40° C. In other embodiments, the temperature at the cell surfacecan be in the range from −20° C. to −80° C., optionally being from −30°C. to −50° C. The tissue is typically maintained at the describedtemperature for a time period in the range from about 1 to about 60seconds, often being from 1 second to 10 seconds, preferably from 2seconds to 5 seconds. Hyperplasia inhibiting efficacy may be enhanced byrepeating cooling in cycles, typically with from about 1 to 5 cycles,with the cycles being repeated at a rate of about one cycle every 60seconds. In the case of arteries, the cooling treatment will usually beeffected very shortly after angioplasty, arthrectomy, rotationalarthrectomy, laser angioplasty, stenting, or another primary treatmentprocedure, preferably within one hour of the primary treatment, morepreferably within thirty minutes within the primary treatment, and mostpreferably immediately following the primary treatment.

The methods of the present invention may be performed with cryosurgicalcatheters comprising a catheter body having a proximal end, a distalend, and a primary lumen therethrough. The primary lumen terminates in aJoule-Thomson orifice at or near its distal end, and a balloon isdisposed over the orifice on the catheter body to contain a cryogenicfluid delivered through the primary lumen. Suitable cryogenic fluidswill be non-toxic and include liquid nitrogen, liquid nitrous oxide,liquid carbon dioxide, and the like. By delivering the cryogenic fluidthrough the catheter body, the balloon can be expanded and cooled inorder to effect treatments according to the present invention.

Preferably, the Joule-Thomson orifice will be spaced inwardly from eachend of the balloon and the balloon will be sufficiently long so that thecooling of the balloon occurs primarily in the middle. The temperatureof the proximal and distal ends of the balloon will thus be much lessthan that of the middle, and the ends will thus act as “insulating”regions which protect luminal surfaces and other body structures fromunintended cooling. Preferably, the balloon has a length of at least 1cm, more preferably at least 2 cm, and typically in the range from 3 cmto 10 cm. The orifice is usually positioned at least 0.5 cm from eachend, preferably being at least 1 cm from each end in balloons which are2 cm or longer.

While it has been found that positioning of the Joule-Thomson valve inthe central region of a balloon will usually provide sufficientinsulation of each end resulting from the inherent heat transfercharacteristics, in some instances it will be desirable to provide aseparate containment bladder nested inside the balloon to receive thecryogenic fluid. The containment bladder will further act to limitcooling to the central region of the balloon. The portions of theballoon proximal and distal to the containment bladder may optionally beinflated with an insulating medium, such as a gas, silicone oil, saline,or the like. Alternatively, the containment bladder may have a vent orbe partially porous so that the cryogenic fluid (which is present as agas within the containment bladder) flows at a controlled rate into theoverlying balloon. By limiting the flow rate, the temperature of thecryogenic fluid will be significantly higher in the regions outside ofthe containment bladder but still within the balloon.

In another aspect, the present invention provides a cryosurgical systemcomprising a flexible catheter body having a proximal end, a distal end,and a gas exhaust lumen defining an axis therebetween. An intravascularballoon is disposed near the distal end of the catheter body in fluidcommunication with the exhaust lumen. The balloon is expandable toradially engage a surrounding vessel wall. A cryogenic cooling fluidsupply is in fluid communication with at least one port disposed withinthe balloon.

As described above, the at least one port may optionally comprise aJoule Thompson orifice. Alternatively, the at least one port may passsome or all of the cryogenic cooling fluid as a liquid. In fact, aplurality of ports may spray the fluid radially, the liquid in somecases distributed substantially uniformly over an inner surface of theballoon wall so that enthalpy of vaporization of the liquid cools aregion of the balloon wall. The vaporization of the liquid will help toinflate the balloon, while the exhaust lumen limits pressure within theballoon to safe levels.

In another aspect, the invention provides a cryosurgical catheter foruse in a blood vessel having a vessel wall. The cryosurgical cathetercomprises a flexible catheter body having a proximal end, a distal end,and a gas exhaust lumen defining an axis therebetween. A balloon isdisposed at the distal end of the catheter body in fluid communicationwith the exhaust lumen. The balloon has a balloon wall with proximal anddistal ends and a radially oriented region extending therebetween. Thewall is radially expandable to engage the surrounding vessel wall. Atleast one cooling fluid distribution port is in communication with acryogenic cooling fluid supply. The at least one port is disposed withinthe balloon to cool the region of the expanded balloon wall.

The cryosurgical methods and catheters of the present invention willoften be tailored to provide even cooling along at least a portion of avascular wall engaged by the cooled balloon. For example, the efficacyof cryogenic cell growth inhibition may be enhanced significantly bydistributing cooling within the balloon using a plurality of cryogenicfluid ports distributed circumferentially and/or axially within theballoon so that a significant portion of the vessel wall engaging theballoon surface is cooled to the target temperature range for a time inthe desired treatment period range.

In this aspect, the present invention provides a cryosurgical catheterfor use in a blood vessel having a vessel wall. The cryosurgicalcatheter comprises a flexible catheter body having a proximal end, adistal end, and a lumen defining an axis therebetween. A balloon isdisposed at the distal end of the catheter body. The balloon is in fluidcommunication with the lumen, and has a balloon wall that expandsradially to engage the surrounding vessel wall. A plurality of coolingfluid distribution ports are in communication with a cooling fluidsupply. These ports are distributed within the balloon so as to evenlycool a portion of the vessel wall.

To maximize cooling efficiency and minimize gas pressure within theballoon, it is generally preferable to minimize the total cooling fluidflow out of the exhaust lumen from the balloon. Efficiency can also beenhanced by directing the cooling fluid radially against the balloonwall, ideally using a plurality of ports that are separatedcircumferentially about a diffuser head. When treating long diseasedsegments of the vasculature, for example, when treating hyperplasia ofthe iliac or superior femoral arteries, it would be beneficial to treatthe entire segment without moving or repositioning the balloon. Toprovide even treatment within such an elongated diseased vessel, thediffuser head may be moved axially within the inflated balloon bysliding a cooling fluid supply tube axially within the catheter body.Such a structure may provide a variety of controllable sequentialcryogenic treatment regimens, for example, multiple temperature feedbackcontrolled cryogenic treatment cycles for inhibiting cell proliferation,or for a variety of alternative endoluminal cryogenic therapies.Alternatively, a fixed diffuser head defining an axially andcircumferential distributed array of ports may provide simultaneous evencooling throughout a significant region of the target site.

In a related method aspect, the invention provides a therapy fortreatment of a blood vessel having a vessel wall. The method comprisesintroducing a catheter into the blood vessel, and expanding a balloon ofthe catheter near a target site to engage the vessel wall. Fluid isexpanded at a first location within the balloon. Fluid is also expandedat a second location within the balloon to cryogenically cool a portionof the engaged vessel wall, the second location being separated from thefirst location.

Gas expansion may effect cryogenic cooling via Joule-Thompson expansionas the cryogenic fluid enters the balloon and/or via the enthalpy ofvaporization of a cryogenic fluid within the balloon. There may besignificant temperature transients when cryogenic cooling is firstinitiated from within the balloon catheter. To enhance the surgeon'scontrol over the cooling rate and treatment time of these cryogenictherapies, gas expansion may be initiated while a moveable orifice headis disposed within a housing or shield at one end of the balloon. Thishousing may conveniently be formed by extending a tubular structuredistally from the catheter body into the interior of the balloon. Such ahousing structure may also be used to help direct exhaust gasesproximally out of the balloon without causing excessive cooling at theproximal end of the balloon, which exhaust gases might otherwise freezeblood within the vessel.

In yet another aspect, the invention also provides a kit for treatinghyperplasia or neoplasia in a body lumen. The kit comprises a catheterhaving a proximal end, a distal end, and balloon near its distal end.Instructions are included in the kit for use of the catheter. Theseinstructions comprise the step of cooling an inner surface of the bodylumen with the balloon to a temperature and for a time sufficient toinhibit subsequent cell growth. Such a kit may include instructions forany of the methods described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a cryosurgical catheter constructed in accordancewith the principles of the present invention, with a distal end shown incross-section.

FIG. 2 is a cross-sectional view of the catheter taken along line 2—2 inFIG. 1.

FIG. 3 illustrates the expansion of a cryogenic fluid within the balloonof the cryosurgical catheter of FIG. 1.

FIG. 4 is a graph illustrating the temperature profile of the balloon ofFIGS. 1 and 3 while liquid nitrogen is being expanded therein and theballoon is present in a body lumen.

FIG. 5 illustrates the distal end of a cryosurgical catheter constructedin accordance with the principles of the present invention and having anested containment bladder within a balloon structure.

FIGS. 6A-6C illustrate use of the catheter of FIG. 1 in treating atarget site within a patient's vasculature.

FIG. 7 is a partial cross-section of a cryosurgical catheter having adiffuser head with a plurality of radially oriented cryogenic fluidports, in which the diffuser head can slide axially within the balloonto provide even cooling of elongate treatment sites.

FIG. 8 is a partial cross-sectional view of a cryosurgical catheterhaving a moveable diffuser head which can be drawn proximally into ahousing within the balloon so as to avoid transients upon initiation ofthe cooling fluid flow.

FIG. 9 schematically illustrates an alternative fixed porous diffuserdefining an axial and circumferential array of orifices.

FIG. 10 illustrates a cross-section of the catheter of FIG. 9.

FIG. 11 illustrates a proximal end of the catheter of FIG. 9.

FIG. 12 illustrates an alternative fixed diffuser structure having anarray of axially separated cryogenic fluid ports.

FIG. 13 is a functional block diagram illustrating the operation of thecatheter of FIG. 7, including an optional feedback control loop.

FIG. 14 schematically illustrates a kit including a balloon catheter andinstructions for its use according to the methods described herein.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

An exemplary cryosurgical catheter 10 constructed in accordance with theprinciples of the present invention is illustrated in FIGS. 1 and 2. Thecatheter 10 comprises a catheter body 12 having a proximal end 14, adistal end 16, and an inflatable balloon 18 disposed at the distal end.The balloon 18 is shown to be an integral extension of the catheter body12, but such a structure is not required by the present invention. Theballoon could be formed from the same or a different material and, inthe latter case, attached to the distal end of the catheter body 12 bysuitable adhesives, heat welding, or the like. The catheter body may beformed from conventional materials, such as polyethylenes, polyimides,and copolymers and derivatives thereof. The balloon may also be formedfrom conventional materials used for angioplasty balloons, typicallybeing non-distensible, such as polyethylene terephthalate (PET).

Catheter 10 comprises a central shaft 20 which may be formed frompolymeric material, such as polyethylene, polytetrafluoroethylene,polyimide, or from a metal, such as from hypotube. In the embodiment ofcatheter 10, the coaxial shaft 20 is tubular and provides a guidewirelumen for positioning of the catheter over a guidewire in a conventionalmanner. The shaft 20, however, could have a variety of otherconfigurations and purposes. For example, the shaft could be a solidwire or core and further optionally provide a guidewire tip at itsdistal end. The shaft could also provide a lumen for deliveringcryogenic fluid to the balloon 18. In the illustrated embodiment of FIG.10, however, the cryogenic fluid is provided by a separate cryogenicfluid delivery tube 22 which is disposed in parallel to the coaxialshaft 20.

The catheter 10 will usually further comprise a thermocouple 24 which isoptimally located near the center of balloon 18. At this location, itcan measure the temperature of the cryogenic fluid after expansion fromthe proximal end of the cryogenic delivery tube 22. The cryogenicdelivery tube 22 will define an expansion orifice at its distal end 23.Thus, the cryogenic fluid will flow through the tube 22 as a liquid atan elevated pressure and (thus inhibiting flow restrictive film boiling)will expand across the orifice 23 to a gaseous state at a lower pressurewithin the balloon. For liquid nitrogen, the pressure within the tube 22will typically be in the range from 50 psi to 500 psi at a temperaturebelow the associated boiling point. After expansion, the nitrogen gaswithin the balloon near its center (the location of thermocouple 24) thepressure will typically be in the range from 30 psi to 100 psi and thetemperature in the range from −40° C. to −100° C. The temperature maydecrease in both the radially outward direction and in both axialdirections from the center of the balloon. This feature of the presentinvention is better described in connection with FIGS. 3 and 4 below.

A hub 28 is secured to the proximal end 14 of the catheter body 12. Thehub provides for a port 30 for connecting a cryogenic fluid source tothe cryogenic delivery tube 22. The hub further provides a port 32 forexhausting the gaseous cryogenic fluid which travels from balloon 18 ina proximal direction through annular lumen 25. A third port 34 isprovided for thermocouple wires 26. A fourth port 36 at the proximal endof the hub is provided for a guidewire.

Referring now to FIGS. 3 and 4, liquid nitrogen (LN2) is delivered toballoon 18 through the cryogenic delivery tube 22. The liquid nitrogenis delivered at a temperature and pressure within in the ranges setforth above and expands to gaseous nitrogen (GN2) across the expansionorifice into the interior of balloon 18. In the single-balloonembodiment catheter 10, the gaseous nitrogen will serve both to inflatethe balloon 18 and to cool the exterior surface of the balloon in adesired temperature profile. In particular, the balloon dimensions andoperating conditions will be selected to provide a particular balloontemperature profile, an example of which is set forth in FIG. 4. Byexpanding the liquid nitrogen to its gaseous state near the center ofthe balloon, the balloon temperature will be lowest near the center andwill decrease in both axial directions away from the center, as shown inthe temperature profile of FIG. 4.

For treating arterial hyperplasia, a balloon temperature in the rangefrom −20° C. to −80° C., e.g., at about −50° C., for a time period inthe range from 1 second to 10 seconds, may be effective. By deliveringthe liquid nitrogen at a pressure in the range from 50 psi to 500 psiand at a temperature below the boiling point, and expanding the liquidnitrogen to a gas at a pressure in the range from 30 psi to 100 psi, atemperature in the above range at the middle of the balloon will beachieved. Moreover, by extending the balloon by distances of at least0.5 cm, preferably of at least 1 cm, in each direction from the centerof the balloon, the temperatures at the ends of the balloons willgenerally no lower than 0° C. In this way, a desired low temperature canbe maintained at the outer surface of the balloon in a treatment regionnear the center of the balloon, while the distal and proximal ends ofthe balloon act to insulate the colder portions from non-target regionswithin the artery or other body lumen. It will be appreciated that theaxial length of the treatment region of the balloon can be variedconsiderably by varying the length of the balloon and controlling thevolume of liquid nitrogen delivered to the balloon. Exemplary balloonswill have a length in the range from 3 cm to 5 cm, a diameter in therange from 1.5 mm to 4 mm, and will typically receive from 0.08 ml/secto 1.5 ml/sec of liquid nitrogen in the temperature and pressure rangesset forth above.

Referring now to FIG. 5, an alternative balloon assembly 50 will bedescribed. The balloon assembly 50 is disposed at the distal end of acatheter body 52 comprising a shaft 54 and a cryogenic fluid deliverytube 56. A balloon 58 is secured to the distal end of the catheter body52, generally as described above with respect to catheter 10. Incontrast to catheter 10, however, balloon assembly 50 comprises acontainment bladder 60 nested within the balloon 58. The containmentbladder 50 may be a second balloon formed in a manner similar to balloon58, except that it will be shorter and will have proximal and distalends spaced axially inwardly from the proximal and distal ends ofballoon 58. The bladder 60, however, may be disposed of differentmaterials and have different properties. Generally, the containmentbladder is intended to receive and contain the gaseous nitrogen after itis expanded across expansion orifice 62 into the interior thereof. Bycontaining the expanded (cold) gaseous nitrogen within bladder 60, amore distinct temperature transition may be effected between the coldmiddle region of balloon 58 and the less cold distal and proximalregions thereof.

Optionally, the balloon 58 may be separately expanded with an insulatingfluid to further sharpen the temperature transition between thecontainment bladder 60 and the remainder of balloon 58. Alternatively,the containment bladder 60 may include ports or porous regions whichpermit the gaseous nitrogen to pass from the interior of the bladder 60into the interior of balloon 58 in a controlled manner to maintain thedesired temperature transition.

Referring now to FIGS. 6A-6C, use of catheter 10 for treating a targetregion TR within a blood vessel BV will be described. The target regionwill usually have been previously treated by balloon angioplasty orother primary conventional protocol for treating atheroscleroticdisease. Such primary treatment will typically utilize an intravascularcatheter, which catheter will have been removed leaving a guidewire GWin place, as illustrated in FIG. 6A. A catheter 10 is then introducedover the guidewire, as illustrated in FIG. 6B. Liquid nitrogen isintroduced to the catheter 10 from a suitable source 70. The source maybe a Dewar flask or other conventional source. In some instances, itwill be possible to utilize recirculating refrigerated liquid nitrogensources, such as those described in U.S. Pat. Nos. 5,644,502 and5,617,739, the full disclosures of which have been previouslyincorporated herein by reference. The liquid nitrogen (LN2) is deliveredto the catheter 10 and inflates balloon 18, as illustrated in FIG. 6C.Because of the temperature profile of the balloon, cooling of the innerwall of the blood vessel BV will be maximized over a central region CRand diminish in the proximal and distal directions from the centralregion, as illustrated qualitatively by the array of arrows in FIG. 6C.The treatment will be performed at the temperatures and for the timesdescribed thereabove in order to inhibit subsequent hyperplasia of thecells of the lining of the blood vessel. Advantageously, the cryogenicmethods of the present invention will inhibit subsequent cellproliferation without inducing injury and thrombosis which can occur asa result of such injury.

A catheter 80 having a moveable port head or diffuser 82 is illustratedin FIG. 7. In this embodiment, cryogenic fluid ports 23 are separatedcircumferentially about diffuser 82, and are oriented radially so as toenhance the heat transfer between the expanding gas and the wall ofballoon 18. In the embodiment illustrated here, four ports 83 areprovided, and are separated circumferentially from each other by about90°.

To enhance an axial length of a substantially evenly cooled centralregion CR, diffuser head 82 is slidably supported on a shaft or rail 84.Feed tube 22 is affixed to diffuser head 82 and is slidably disposedwithin catheter body 12. A proximal housing 86 at proximal end 14 ofcatheter 80 contains a rack and pinion mechanism 88 which controllablymoves feed tube 22. By rotating control knob 90 (or automaticallydriving rack and pinion mechanism 88 with drive system 92), feed tube 22and diffuser 82 can move from a first position 95 to a second position96 without moving or deflating balloon 18. This allows a relativelysmall fluid flow to cool an elongate central region CR.

Inhibition of cell proliferation along elongate segments of vasculature,such as in the iliac or superior femoral arteries should benefit fromcryosurgical treatment at repeatable temperatures and for repeatabletimes. To help prevent gaps between treatment regions and/or repeatingtreatments unintentionally, it would be advantageous to allow treatmentsof these elongate lumenal walls without moving or repositioning of thecryosurgical catheter. Hence, it is generally desirable to providestructures and methods which can uniformly apply radial cooling alongthese elongate endothelial surfaces.

Safety of endoluminal cryosurgical techniques is generally enhanced byminimizing the flow of the cooling fluid. Low flow rates will generallyreduce the release of gas into the body lumen in the unlikely event of aballoon rupture. Known balloon structures can withstand pressures of upto about 100 psi or more. Nonetheless, safety can be enhanced bylimiting maximum balloon pressures to 100 psi or less, and preferably toless than 100. Lower balloon pressures not only reduce the amount of gasreleased in the event of a rupture, they also help decrease thepossibility of such a balloon rupture occurring. Given a constantcooling fluid pressure at port 83, lower pressures within balloon 18will also produce a lower balloon wall temperature. In other words,cryogenic cooling is generally enhanced by minimizing the pressurewithin the balloon.

As there is a limited cross-sectional area available for exhausting theexpelled gases, pressure within the balloon is most easily minimized bydecreasing the speed (and pressure head loss) of exhaust gases flowingproximally through catheter body 12 to exhaust port 32. Drawing a vacuumat exhaust port 32 can encourage the flow of gases proximally and reduceballoon pressure to some extent, but this will provide limited benefitswhen gas velocity and pressure drops are high within the catheter body.Hence, it is beneficial to make efficient use of a relatively smallcryogenic fluid flow. By moving diffuser 82 axially within balloon 18,an elongate region of the vessel wall can be treated sequentially with amodest cryogenic fluid supply and a low balloon pressure. As the amountof time the tissues are to be cooled is quite short, the total proceduretime remains very reasonable.

The use of moveable diffuser head 82 also allows the surgeon toselectively treat tissues in a highly controlled manner. For example,when balloon 18 extends across a branch artery, the surgeon has theoption of treating the vessel proximally and distally of the branch andshutting off the gas flow when the diffuser is aligned with the branchso as to avoid freezing blood within the branch opening. Additionally,by coupling automated drive system 92 to the actuation mechanism, a widevariety of treatment cycles and times may be controllably and repeatablyeffected.

Balloon 18 of moveable diffuser catheter 80 may be quite elongate, theballoon typically having a length in a range from about 1 to about 10cm. In the exemplary embodiment, the balloon has a length of about 10 cmso that proximal housing 86 and/or actuation mechanism 88 has a strokelength of about 8 cm. To enhance heat flow through balloon 18, a heattransfer enhancing material may be included in the polymer of theballoon wall. For example, the addition of between about 1 and 10% boronnitride in a polyethylene or other balloon polymer can significantlyimprove heat transfer of the entire system. Surprisingly, a significanttemperature differential may be found between an inner and outer surfaceof the balloon during cooling. Hence, improving the thermal conductivityof the balloon material may provide significant benefits.

In the embodiment of FIG. 7, a fixed guidewire 94 extends distally fromthe balloon to help when advancing catheter 80 within the vasculature.Fixed guidewire 94 and the distal end of balloon 18 are affixed to anaxial support or rail 84 which structurally supports the distal end ofthe catheter when the balloon is not inflated. Rail 84 here comprises astainless steel wire with a diameter of 0.008 inches, but mayalternatively comprise a wide variety of shaft structures, optionallyincluding one or more lumens for a moveable guidewire or the like.

Diffuser 82 includes four radially oriented ports, each having adiameter of about 0.0025 inches. These openings are in fluidcommunication with a central passage, which in turn is supplied by feedtube 22. Diffuser head 82 may have an outer diameter of about 0.032inches, and may comprise any of a variety of alternative polymers ormetals. Diffuser 82 is affixed to feed tube 22 by adhesion bonding, heatwelding, fasteners, or the like. In the exemplary embodiment, diffuser82 comprises polyimide. Feed tube 22 may also be formed from a polyimidetube, and will preferably be coated with a PTFE such as Teflon™ to avoidfriction when the feed tube reciprocates within the catheter body.Diffuser head 82 is shown affixed to rail 84 using bands which encirclethe diffuser and define a channel through which rail 84 passes. Clearly,a wide variety of alternative support arrangements are possible,including a concentric support shaft or tube, a cantilevered feed tube,or the like. As described above, thermocouple 24 or some alternativetemperature sensor sends a signal proximally via wire 26 to indicate thetemperature within the balloon.

In use, moveable diffuser balloon catheter 80 will be introduced into ablood vessel while balloon 18 is in an uninflated, small profileconfiguration. Balloon 18 will be maneuvered to the treatment site usingfixed guidewire 94. Feed tube 22 will be positioned so that diffuser 82is located at first position 95, and cryogenic fluid will be advancedthrough feed tube 22 to the diffuser. This gas will inflate balloon 18,and will also cool the interior surface of the balloon and blood vesselas described above. Control knob 90 will be rotated so that diffuser 82moves axially toward position 96. As the cooling fluid exits thediffuser, the endothelial tissue engaging central region CR iscryogenically cooled.

Cryogenic cooling fluid may optionally pass through a Joule-Thompsonorifice adjacent port 83 to effect cooling. In other embodiments, atleast a portion of the cryogenic cooling fluid may exit port 83 into theballoon as a liquid. The liquid will vaporize within the balloon, andthe enthalpy of vaporization can help cool the surrounding vessel wall.The liquid may coat at least a portion of the balloon wall so as toenhance even cooling over at least a portion of the vessel wall. Hence,ports 83 may have a total cross section which is smaller than a crosssection of the fluid supply lumen, or which is at least as large as thecross section of the fluid supply lumen.

By controlling the rate of movement of diffuser 82 via control knob 90,the amount of cooling fluid injected via feed tube 22, and the pressureat exhaust port 32, the surgeon can control the cooling rate of thetissue, the temperature of the tissue, and optionally, the number ofcooling cycles the tissue is subjected to while the catheter is in asingle location. As described above, the ends of the diffuser strokefirst and second positions 95, 96 may be separated from the axial endsof balloon 18 so as to limit any cooling of fluids within the vessel.

As can be understood with reference to FIG. 8, it will be desirable tocontrol the initial rate of cooling when cryogenic fluid first starts toexit diffuser 82. As the balloon inflates and the diffuser structurecools, significant thermal transients will occur before the desiredsteady state cryogenic cooling begins. To avoid unpredictable orexcessively slow cooling rates, diffuser 82 may initially be parkedwithin a housing 98 inside balloon 18. Housing 98 may be formed byextending a tube from catheter body 12 into balloon 18, the housingoptionally comprising an extension of the catheter body material.

An additional benefit of housing 98 may be understood with reference toFIGS. 7, 8, and 4. As cooling gas flows from diffuser 82 into balloon18, the expelled gases are exhausted proximally from the balloon intocatheter body 12. Although the gases will warm as they travelproximally, the gas flow will be accelerating from their relativelylarge cross-sectional diameter of the balloon into the catheter body.This may actually enhance cooling adjacent the proximal end of theballoon, and could freeze blood proximally of the balloon.

To avoid this enhanced proximal cooling, housing 98 admits gases from acentral location along central region CR. The gases surrounding housing98 within balloon 18 are allowed to stagnate near the proximal end ofthe balloon, thereby limiting axial cooling at that location.

As described above, there may be a significant temperature differentialbetween the inner surface and the outer surface of the balloon wall. Tomore accurately and repeatably monitor cryosurgical therapy, atemperature sensor 24 is mounted on the outer surface of the balloon tomeasure the temperature of the tissue at the target site, the tissueballoon interface, and/or the balloon outer surface temperature.

Referring now to FIG. 9, a fixed diffuser 100 includes an array of ports83 which are distributed both axially and circumferentially around thediffuser. As ports 83 are radially oriented, diffuser 100 will achievethe desired cooling of the surrounding tissue with relatively lowballoon pressures and low cooling fluid flow rates. As the cryogenicliquid or gas-liquid combination is directed perpendicularly against thewall of balloon 18, the heat transfer coefficient between the gas andthe balloon wall is quite high. This helps to reduce temperature of theballoon and provides greater heat extraction for a given flow rate ofcoolant into the balloon. Additionally, as ports 83 are distributed bothcircumferentially and axially along the balloon, diffuser 100 willdistribute the cooling more uniformly over the surface of the balloon soas to produce a uniform antiproliferative response.

Diffuser 100 will generally comprise a tubular structure with radiallyoriented openings. An exemplary tubular structure may comprise apolyimide tube having an inner diameter of about 0.032 inches and a wallthickness of 0.001 inch. Each port will again define a diameter of about0.0025 inches. There will typically be between about 6 and 600 orificesin diffuser 100. In the exemplary embodiment, four axial rows oforifices are separated by about 90° from each other. The rows areaxially staggered so that the orifices in a single row have centerlineseparations of about 4 mm, while the orifices of adjacent rows areseparated by about 2 mm. The overall length of the porous diffuser tubeis about 2 cm.

A central shaft 104 having a guidewire lumen 106 is bondedconcentrically to diffuser 100 using adhesive or the like at the distalend of the diffuser, and optionally also at the proximal end of thediffuser. High contrast markers 102 may be provided to enhance an imageof the catheter so as to facilitate positioning of balloon 18fluroscopically, sonographically, or under any other alternative imagemodality (with appropriate contrast structures). The distal marker mayoptionally be formed by winding a gold or platinum wire around thecentral shaft and bonding the gold wire to the distal end of thediffuser tube. The proximal marker may similarly be formed by windingand bonding a gold or platinum wire, the proximal marker optionallybeing disposed over the diffuser tube so that the cryogenic coolingfluid may be introduced through the annular space between the diffusertube and the central shaft proximally of the balloon. Central shaft 104will typically comprise a polyimide tube, but may alternatively compriseany of a wide variety of materials.

The coaxial arrangement between diffuser 100 and central shaft 104 (withan annular cooling fluid flow path between the tube of the diffuser andthe central shaft) promotes circumferentially symmetric distribution ofthe cryogenic cooling fluid against the balloon wall, which in turnprovides a more circumferentially even temperature distribution. Asgenerally described above, uniform temperature distributions, bothaxially and circumferentially, within central region CR (see FIG. 4)help ensure that the beneficial inhibition of cell proliferation isprovided throughout a significant portion of the tissue engaged byballoon 18. To limit cooling of tissues or fluids disposed axially ofthe balloon, distal and proximal stagnant regions within the balloonflow profile are created by the shape and configuration of diffuser 100,balloon 18, and by the presence of housing 98 within the proximal end ofthe balloon, as described above. Even though no moveable diffuser willbe drawn into housing 98, this structure still helps to avoid theaccelerating flow of gases along the proximally tapering balloon wall.

To accurately control the cooling process, it is beneficial to monitorpressure within the balloon. Toward that end, a balloon pressure port108 transmits pressure proximally via a pressure monitoring lumen 110,as can be understood with reference to FIGS. 9 and 10. Accuracy of suchpressure monitoring can be enhanced by minimizing the flow of fluidproximally within the pressure monitoring lumen. Alternatively, apressure transducer may be mounted within the balloon with wires sendinga pressure signal proximally. Within the elongate catheter body 12,lumens for the cryogenic feed tube 22, pressure monitoring port 108,guidewire and the like may be contained within an insulated jacket 112.As balloon 18 may elongate when inflated, and as the distal end ofdiffuser is affixed to the distal end of the balloon by core shaft 104,it may be beneficial to allow jacket 112 to slide axially withincatheter body 12 to avoid axial bending of the balloon and the resultingradially uneven cooling. In alternative embodiments, a cryogenic feedtube may simply extend distally into an annular space between a centralshaft and a jacket formed as a continuous proximal extension of thediffuser tube, with any proximal leakage of the cooling fluid within thejacket optionally being exhausted into the catheter body and removed viathe exhaust lumen.

Referring now to FIG. 11, a proximal end of the fixed diffuser catheterillustrated in FIGS. 9 and 10 include many of the coupling structuresdescribed above regarding FIGS. 1 and 7. Guidewire port 114 providesproximal access to guidewire lumen 106, while a pressure monitoringconnector 116 is in fluid communication with the interior of balloon 18via monitoring lumen 110. Where balloon pressures are acceptable,cryogenic cooling may optionally be controlled using an orifice disposedat exhaust port 32. This proximal structure can be assembled fromcommercial available components using potting adhesive 118 in agenerally conventional manner.

Referring now to FIG. 12, still further alternative multiple orificediffuser structures are possible. In this embodiment (illustrated herewithout balloon 18) a series of ports 83 are distributed axially so asto distributed the cooling axially within an elongate target region, asgenerally described above. In this embodiment, a series of individualgas feed tubes 120 supply the cryogenic cooling fluid to the ports, witheach port optionally having an opening which has the same area as thelumen of the associated gas feed tube. Such individual feed tubes maycomprise polyimide tubes having an inner diameter of about 0.005 inches.In some embodiments, axial distribution of cooling may be controlled byvarying the amount of fluid expelled from each port, by varying theinterorifice spacing (axially and/or circumferentially), by locallyvarying the heat transfer coefficient or cooling fluid pattern, or thelike.

It will generally be beneficial to make use of catheter 80 as onecomponent of an integrated cryosurgical endoluminal therapy system 130.As the actual tissue cooling may vary with pressures within the balloon,cooling fluid flow rates, and the like, and as these parameters may varywhen catheter body 12 is bent in following the vasculature system, theefficacy of the cryosurgical therapy may be enhanced by adjusting thetreatment based on measured characteristics of the cooling process, forexample, based on temperatures measured by one or more temperaturesensors 24. Hence, electrical temperature signals 132 from temperaturesensors 24 may be directed to a controller 134 for use in a feedbackcontrol system. Preferably, controller 134 processes the temperaturesignals to generate cooling fluid feed signals 136 indicating thepressure or volume of cryogenic fluid to be injected into the catheter.Controller 134 will preferably also provide electrical signals whichdirect diffuser drive 92 to mechanically reposition diffuser 82, andwill often provide signals varying the pressure (or vacuum) at exhaustport 32. These signals may be used not only to vary the cooling cycle,but can also be used to control the inflation and/or deflation of theballoon, preferably based at least in part on a pressure monitored fromwithin the balloon.

To inhibit cell proliferation and/or remodeling, controller 134 willgenerally initiate, monitor, and control cooling of the tissue.Cryogenic system 130 will often be used to effect a cooling rate of thetissue in a range from about 2 to about 30° C. per second. In anexemplary cell proliferation inhibition therapy, the system willmaintain the tissue at a temperature in a range from about 0 to about−80° C., preferably at a temperature in a range from about −10 to about−40° C., for a time between about 1 and about 60 seconds. The efficacyof the therapy may be enhanced by repeatedly cooling the tissue to thesetemperatures for between 1 and 5 cooling cycles, typically repeating thecooling cycles at the rate of 1 every 60 seconds. To provide thiscooling, cryogenic liquids or liquid/gas mixtures comprising carbondioxide, nitrous oxide, or the like may flow through the balloon at arate in a range from about 100 to about 800 mg/sec. Such cooling mayinhibit cell proliferation via processes which are sometimes referred toas apoptosis and/or programmed cell growth.

A kit 140 including balloon catheter 10 and instructions for its use 142is illustrated in FIG. 14. Catheter 10 may be replaced by any of theballoon catheter structures described above, while instructions for use142 may describe any of the associated method steps set forth above forinhibition of cell proliferation. Instructions for use 142 will often beprinted, optionally appearing at least in part on a sterile package 144for balloon catheter 10. In alternative embodiments, instructions foruse 142 may comprise a machine readable code, digital or analog datagraphically illustrating or demonstrating the use of balloon catheter 10to inhibit hyperplasia, or the like. Still further alternatives arepossible, including printing of the instructions for use on packaging146 of kit 140, and the like.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. For example, one or more radial orifices might move bothcircumferentially and axially within the balloon, optionally along ahelical path, to provide cylindrically even cooling. Therefore, theabove description should not be taken as limiting the scope of theinvention which is defined by the appended claims.

1. A method for treating a blood vessel having a vessel wall, the methodcomprising: introducing a catheter into the blood vessel; expanding aballoon of the catheter near a target site within the vessel wall, theballoon having a balloon wall; cooling the vessel wall with the balloonby coating at least a portion of an inner surface of the balloon wallwith a liquid so that the liquid coating vaporizes, the coating engagingthe balloon wall within the balloon.
 2. The method of claim 1, furthercomprising; expanding the liquid at a first location within the balloon;and expanding the liquid at a second location within the balloon tocryogenically evenly cool the engaged vessel wall, the second locationbeing circumferentially separated from the first location.
 3. The methodof claim 2, further comprising moving a diffuser head between the firstlocation and the second location.
 4. The method of claim 3, wherein ahousing separates the balloon and the vessel wall when the orifice headis at the first location, wherein fluid expansion is initiated at thefirst location, and wherein the moving step moves ports of the diffuserhead from within the housing after a reduction in thermal of the gasexpansion.
 5. The method of claim 2, wherein fluid expansion occurssimultaneously at the first and second locations, the balloon beingaxially elongate, the first and second locations being separatedaxially.
 6. The method of claim 2, wherein the fluid expansion occurssimultaneously at the first and second locations so that the fluid flowsradially toward the vessel wall.
 7. The method of claim 2, wherein thefirst and second expansion steps comprise vaporization of at least aportion of the fluid from a liquid to a gas so that the enthalpy ofvaporization cools the at least a portion of the engaged vessel wall. 8.A method for treating a blood vessel having a vessel wall, the methodcomprising: introducing a catheter into the blood vessel; expanding aballoon of the catheter near a target site within the vessel wall, theballoon having a balloon wall; cooling the vessel wall with the balloonby coating at least a portion of an inner surface of the balloon wallwith a liquid, the liquid vaporizing within the balloon.
 9. The methodof claim 8, wherein the at least a portion of the inner surface of theballoon wall is coated by introducing a cryogenic cooling fluid througha port into balloon so that at least a portion of the cryogenic coolingfluid exits the port as the liquid.
 10. The method of claim 9, whereinthe liquid coats the at least a portion of the inner surface of theballoon wall so as to enhance even cooling over at least a portion ofthe vessel wall engaged by the balloon.
 11. The method of claim 10,wherein the liquid coating the balloon wall vaporizes while the coatingengaged the balloon wall within the balloon.